Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease.

Abstract

The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ1-42 was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ1-42. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.

• Authors: Li-Cheng Zhou, Ying-Fan Liang, Yi Huang, Gui-Xiang Yang, Lu-Lu Zheng, Jia-Min Sun, Yang Li, Fu-Li Zhu, He-Wen Qian, Rui Wang, Lei Ma
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 219 Pg. 113426 (Jul 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33848787 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Indoles
• Neuroprotective Agents
• Peptide Fragments
• Reactive Oxygen Species
• amyloid beta-protein (1-42)
• Hydrogen Peroxide
• Diosgenin

Topics

• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (chemistry, metabolism, pharmacology)
• Animals
• Binding Sites
• Blood-Brain Barrier (drug effects, metabolism)
• Cell Survival (drug effects)
• Diosgenin (chemistry)
• Disease Models, Animal
• Drug Design
• Humans
• Hydrogen Peroxide (pharmacology)
• Indoles (chemistry)
• Male
• Maze Learning (drug effects)
• Mice
• Mice, Inbred ICR
• Molecular Docking Simulation
• Neuroprotective Agents (chemical synthesis, therapeutic use)
• Peptide Fragments (chemistry, metabolism, pharmacology)
• Reactive Oxygen Species (metabolism)
• Structure-Activity Relationship